Randomized, Double‑Blind, Placebo‑Controlled Phase 3 Trial of Oral Votoplam in Adults with Huntington’s Disease Assessing cUHDRS Progression

The primary objective is to evaluate the effect of votoplam versus control on Huntington’s disease progression by measuring change in the composite Unified Huntington’s Disease Rating Scale (cUHDRS). Secondary objectives include assessment of functional decline using the UHDRS‑Total Functional Capacity score, loss of independence measured by the UHDRS‑Independence Scale, overall disease progression, motor symptom progression via the UHDRS‑Total Motor Score, cognitive decline assessed with the Symbol Digit Modality Test and the Stroop Word Reading Test, pharmacodynamic reduction of mutant huntingtin protein in blood, neurodegeneration evaluated by serum NfL, and the safety and tolerability profile of votoplam compared with placebo.

The trial enrolled 447 ambulatory participants, both male and female, aged 21 to 70 years, who were diagnosed with genetically confirmed Huntington’s Disease (CAG repeat length ≥40). Selection required a documented CAG repeat count obtained before screening and baseline disease characteristics meeting predefined thresholds (UHDRS total functional capacity score = 13, UHDRS total motor score 7–25, UHDRS independence scale ≥90, and CAP100 ≥70). All individuals provided signed informed consent prior to inclusion. Participants were required to be in a generally stable health condition permitting ambulatory activity, with no additional lifestyle restrictions specified in the protocol.

The study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy, safety and tolerability of votoplam (HTT227) in participants with Huntington’s disease. After obtaining signed informed consent, participants undergo a screening visit to confirm eligibility, record baseline assessments, and collect genetic confirmation of CAG repeat length. Eligible subjects are then randomized in a 1:1 ratio to receive either votoplam tablets or matching placebo and begin the treatment phase. Study visits are scheduled at baseline (Day 0) and subsequently at months 3, 6, 12, 18, 24, 30, and 36, during which clinical evaluations, the composite Unified Huntington’s Disease Rating Scale (cUHDRS) assessment, laboratory tests, and safety monitoring are performed. The final visit at month 36 serves as the end‑of‑study assessment. Participant involvement therefore extends for approximately 36 months plus the initial screening period. Early termination may occur if a participant experiences a serious adverse event, withdraws consent, fails to comply with protocol‑required procedures, or meets predefined discontinuation criteria based on disease progression or safety concerns.

The investigational product, identified as HTT227, contains the active substance votoplam in a tablet formulation for oral administration. Each tablet is specified to contain 0 mg of the active ingredient and is to be taken by mouth according to the dosing schedule defined in the protocol.

The control arm receives a matching placebo tablet that contains no active pharmaceutical ingredient. The placebo is identical in appearance to the investigational tablet and is administered by the same oral route.

Dosing is performed once daily; the exact timing is recorded in the study diary. Compliance is monitored through pill counts at each study visit and verification of diary entries. All administrations are conducted in a double‑blind manner to maintain blinding of participants and investigators.

The trial enrolls participants with a diagnosis of Huntington’s Disease and evaluates the effect of votoplam on disease progression using the composite Unified Huntington’s Disease Rating Scale (cUHDRS) as the primary efficacy endpoint.

The primary efficacy assessment will compare the change from baseline to month 36 in the composite Unified Huntington’s Disease Rating Scale (cUHDRS) score between the investigational product and placebo groups.

Secondary efficacy evaluations will include the change from baseline to month 36 in the following parameters: total functional capacity (UHDRS‑TFC), independence scale (UHDRS‑IS), total motor score (UHDRS‑TMS), Symbol Digit Modalities Test (SDMT), Stroop Word Reading Test (SWRT), percent change in blood mutant huntingtin (mHTT) protein at steady state, and change in serum neurofilament light chain (NfL). Additionally, the time to a decline of at least one point in TFC or at least ten points in IS will be monitored over the treatment period. All clinical rating scales and cognitive tests are administered by trained assessors using validated instruments at baseline and at month 36, with interim monitoring for the time‑to‑event endpoint throughout the study. Biomarker concentrations will be quantified using standardized laboratory assays on blood samples collected at baseline and at month 36.